Excitatory projections from the prefrontal cortex (PFC) to the ventral tegmental area (VTA) play an important role in regulating the activity of VTA neurons and the extracellular levels of dopamine (DA) within forebrain regions. Previous investigations have demonstrated that PFC terminals synapse on the dendrites of DA and non-DA neurons in the VTA. However, the projection targets of these cells are not known. To address whether PFC afferents innervate different populations of VTA neurons that project to the nucleus accumbens (NAc) or to the PFC, a triple labeling method was used that combined peroxidase markers for anterograde and retrograde tract-tracing with pre-embedding immunogold-silver labeling for either tyrosine hydroxylase (TH) or GABA. Within the VTA, PFC terminals formed asymmetric synapses onto dendritic shafts that were immunoreactive for either TH or GABA. PFC terminals also synapsed on VTA dendrites that were retrogradely labeled from the NAc or the PFC. Dendrites retrogradely labeled from the NAc and postsynaptic to PFC afferents were sometimes immunoreactive for GABA but were never TH-labeled. Conversely, dendrites retrogradely labeled from the PFC and postsynaptic to PFC afferents were sometimes immunoreactive for TH but were never GABA-labeled. These results provide the first demonstration of PFC afferents synapsing on identified cell populations in the VTA and indicate a considerable degree of specificity in the targets of the PFC projection. The unexpected finding of selective PFC synaptic input to GABA-containing mesoaccumbens neurons and DA-containing mesocortical neurons suggests novel mechanisms through which the PFC can influence the activity of ascending DA and GABA projections.

Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaineinduced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model. C ocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. An enduring cocaine-induced impairment in cognitive control of motivated behavior contributes to the vulnerability to relapse (1, 2). Projections from the frontal cortex to the basal ganglia constitute a primary brain substrate for regulating motivated behavior (3). Cocaine-induced neuropathologies in the projection from the prefrontal cortex to the nucleus accumbens are implicated in cocaine addiction (4), including impaired neuroplasticity and synaptic communication (4,5). For example, prefrontal synapses in the accumbens undergo enduring potentiation (6-9), and the ability of these synapses to increase or decrease synaptic strength is impaired (7, 10). In addition, withdrawal from chronic cocaine use increases both presynaptic release estimated by elevated frequency of miniature excitatory postsynaptic currents (mEPSC) and by postsynaptic strength measured as increases in the surface expression of AMPA glutamate receptors and the ratio of AMPA/NMDA currents at glutamatergic synapses (6,8,11).Neuroimaging in cocaine addicts reveals reduced activity in prefrontal cortex under baseline conditions, but marked hyperresponsiveness in the prefrontal cortex and accumbens that is correlated with a desire for drug upon exposure to drug-associated stimuli (12). Similarly, animal models of relapse show that activation of this pathway is necessary and sufficient to reinstate cocaine-seeking behavior (13) and that neuronal ac...

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Voltage-gated Na+ channels are major targets of G protein-coupled receptor (GPCR)-initiated signaling cascades. These cascades act principally through protein kinase-mediated phosphorylation of the channel alpha subunit. Phosphorylation reduces Na+ channel availability in most instances without producing major alterations of fast channel gating. The nature of this change in availability is poorly understood. The results described here show that both GPCR- and protein kinase-dependent reductions in Na+ channel availability are mediated by a slow, voltage-dependent process with striking similarity to slow inactivation, an intrinsic gating mechanism of Na+ channels. This process is strictly associated with neuronal activity and develops over seconds, endowing neurons with a novel form of cellular plasticity shaping synaptic integration, dendritic electrogenesis, and repetitive discharge.

Dendritically placed, voltage-sensitive ion channels are key regulators of neuronal synaptic integration. In several cell types, hyperpolarization/cyclic nucleotide gated (HCN) cation channels figure prominently in dendritic mechanisms controlling the temporal summation of excitatory synaptic events. In prefrontal cortex, the sustained activity of pyramidal neurons in working memory tasks is thought to depend on the temporal summation of dendritic excitatory inputs. Yet we know little about how this is accomplished in these neurons and whether HCN channels play a role. To gain a better understanding of this process, layer V-VI pyramidal neurons in slices of mouse prelimbic and infralimbic cortex were studied. Somatic voltage-clamp experiments revealed the presence of rapidly activating and deactivating cationic currents attributable to HCN1/HCN2 channels. These channels were open at the resting membrane potential and had an apparent half-activation voltage near Ϫ90 mV. In the same voltage range, K ϩ currents attributable to Kir2.2/2.3 and K ϩ -selective leak (K leak ) channels were prominent. Computer simulations grounded in the biophysical measurements suggested a dynamic interaction among Kir2, K leak , and HCN channel currents in shaping membrane potential and the temporal integration of synaptic potentials. This inference was corroborated by experiment. Blockade of Kir2/K leak channels caused neurons to depolarize, leading to the deactivation of HCN channels, the initiation of regular spiking (4 -5 Hz), and enhanced temporal summation of EPSPs. These studies show that HCN channels are key regulators of synaptic integration in prefrontal pyramidal neurons but that their functional contribution is dependent on a partnership with Kir2 and K leak channels.

Patient and proxy ratings were concordant when rating patients' ability to perform PADLs. Moreover, concordance was extremely high on IADLs when patients' Folstein scores were 24 or higher. Concordance with respect to IADLs was relatively poor only among patients with Folstein scores below 24. In that case, patients had a more optimistic view of their independence, compared with their proxies.

Although automobiles remain the transportation of choice for older adults, late life cognitive impairment and dementia often impair the ability to drive safely. There is, however, no commonly utilized method of assessing dementia severity in relation to driving, no consensus on the assessment of older drivers with cognitive impairment, and no gold standard for determining driving fitness. Yet, clinicians are called upon by patients, their families, other health professionals, and often the Department of Motor Vehicles (DMV) to assess their patients' fitness-to-drive and to make recommendations about driving privileges. Using the case of Mr W, we describe the challenges of driving with cognitive impairment for both the patient and caregiver, summarize the literature on dementia and driving, discuss evidenced-based assessment of fitness-to-drive, and address important ethical and legal issues. We describe the role of physician assessment, referral to neuropsychology, functional screens, dementia severity tools, driving evaluation clinics, and DMV referrals that may assist with evaluation. Finally, we discuss mobility counseling (eg, exploration of transportation alternatives) since health professionals need to address this important issue for older adults who lose the ability to drive. The application of a comprehensive, interdisciplinary approach to the older driver with cognitive impairment will have the best opportunity to enhance our patients' social connectedness and quality of life, while meeting their psychological and medical needs and maintaining personal and public safety.

This study provides longitudinal evidence for a decline in driving performance over time, primarily in early-stage DAT, and supports the need not only for driving assessments, but also for reevaluation of individuals with very mild and mild DAT.